The role of macrophage cell death in tuberculosis

Abstract

Studies of host responses to infection have traditionally focused on the direct antimicrobial activity of effector molecules (antibodies, complement, defensins, reactive oxygen and nitrogen intermediates) and immunocytes (macrophages, lymphocytes, and neutrophils among others). The discovery of the systems for programmed cell death of eukaryotic cells has revealed a unique role for this process in the complex interplay between microorganisms and their cellular targets or responding immunocytes. In particular, cells of the monocyte/macrophage lineage have been demonstrated to undergo apoptosis following intracellular infection with certain pathogens that are otherwise capable of surviving within the hostile environment of the phagosome or which can escape the phagosome. Mycobacterium tuberculosis is a prototypical`intracellular parasite' of macrophages, and the direct induction of macrophage apoptosis by this organism has recently been reported from several laboratories. This paper reviews the current understanding of the mechanism and regulation of macrophage apoptosis in response to M. tuberculosis and examines the role this process plays in protective immunity and microbial virulence.

Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages

“…These bacteria evade the immune response and survive in the host by controlling the type of cell death in infected macrophages. 2,3 While apoptosis of infected macrophages is considered beneficial for controlling bacterial growth and stimulating the adaptive immune response, necrosis of macrophages helps disseminate bacteria. 3,34 Virulent Mycobacterium tuberculosis manipulates host cell death mechanisms by inducing the expression of Mcl-1.…”

“…2,3 While apoptosis of infected macrophages is considered beneficial for controlling bacterial growth and stimulating the adaptive immune response, necrosis of macrophages helps disseminate bacteria. 3,34 Virulent Mycobacterium tuberculosis manipulates host cell death mechanisms by inducing the expression of Mcl-1. 19 We used PPD treatment and BCG infection to study the involvement of Notch signaling and Mcl-1 in macrophages.…”

“…1 Apoptosis of macrophages is one of the defense mechanisms of the host that eliminates both the infected cells and the bacteria residing inside these cells. 2,3 Furthermore, apoptotic macrophages are critical for inducing adaptive immune responses, as apoptotic vesicles containing mycobacteria are phagocytized by nearby antigen-presenting cells and presented to CD8 1 T cells. 4,5 Apoptosis of macrophages in this setting is partially tumor-necrosis factor-dependent.…”

Mycobacterial 19-kDa lipoprotein mediates Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages at early stages of infection

“…5 In this context, monocyte/macrophage apoptosis has been reported to be associated with mycobacterial survival rather than to its killing. 3 On these grounds, it would be of interest to identify the mycobacterial molecule/s delivering death signals in monocytes.…”

Pathogenic and opportunistic respiratory bacteria-induced apoptosis

“…tuberculosis also protects cells against apoptosis via two key pathways: induction of the TLR-2-dependent activation of the NFkB cell survival pathway and enhancement of the production of the soluble TNF receptor 2 (sTNFR2), which neutralizes the pro-apoptotic activity of TNFα [31,32]. Therefore, modulation of the apoptotic pathways by M. tuberculosis is complex and includes both the induction of cell-death and cell-survival signals.…”